Optimising Outcomes in Gastrointestinal Neuroendocrine Tumours · of the neuroendocrine system Most...

OPTIMISING OUTCOMES IN GASTROINTESTINAL NEUROENDOCRINE TUMOURS

Dr Mairéad McNamara

Senior lecturer, University of Manchester & Honorary Consultant

in Medical Oncology, The Christie NHS Foundation Trust

The future

Targeted molecular therapy Research

Multidisciplinary approach

Investigations Treatment

What are neuroendocrine tumours?

Classification Symptoms

NEUROENDOCRINE TUMOURS:

OPTIMISING OUTCOMES

THE NEUROENDOCRINE SYSTEM

Neuro = nerve

Endocrine = network of glands

and organs in the body that

produce hormones

Neuroendocrine cells found in

endocrine glands – adrenal

glands, pancreas, thyroid,

pituitary and in ovaries and

testes

Source: http://cnx.org/content/col11496/1.6/; licensed under

the Creative Commons Attribution 3.0 Unported license

Source: http://www.ipsen.co.uk/ipsen_net.php;

reproduced with permission from Ipsen

Neuroendocrine tumour (NET) = tumour

of the neuroendocrine system

Most common locations are in the lungs

and digestive system

“Carcinoid” – when tumours arise in the

tubular gastrointestinal (GI) tract

Pancreatic neuroendocrine tumours

(pNETs) when they arise in the

pancreas

Gastrinomas when they arise in the

proximal portion of the duodenum

The more accurate description is NET

or gastroenteropancreatic (GEP) NET

(two categories – tumours of luminal GI

tract and pNETs)

NEUROENDOCRINE TUMOURS

https://images.google.com

Mid-1800s – first identified

1907 – “Carcinoid” – a tumour that

grew much more slowly than usual

cancers

1950s – could spread from one part of

the body to another like other forms of

cancer

1952 – carcinoid heart disease

identified1

1953 – flushing effect of serotonin

became clinically recognised1


HISTORY

1. Modlin IM, et al., Human Pathology 2004; 35:1440-51.

2005

NET incidence by primary site


INCIDENCE

Rare, incidence rising1 possibly due to

increased detection of asymptomatic

disease

As diagnostic imaging increases in

sensitivity, very small insignificant

NETs may be coincidentally

discovered

Most are sporadic (causes unknown)

but patients with multiple endocrine

neoplasia (MEN), neurofibromatosis

type 1 and von Hippel Lindau (VHL)

are at increased risk

1. Yao JC, et al., J Clin Oncol. 2008; 26:3063-72. Reprinted with permission. © 2008, American Society of Clinical Oncology. All rights reserved.



CLASSIFICATION

NETs often grow slowly and it may take

years before symptoms appear and tumour

is diagnosed; well-differentiated

Some NETs may be fast-growing;

poorly-differentiated

ENETS / WHO 2010

Nomenclature and classification for digestive system NET

Tumour

differentiationGrade

Mitotic count

(in 10 high-power

fields)

Ki-67 index

(%)ENETS / WHO classification

Well-

differentiated

1 Low < 2 < 3Neuroendocrine tumour,

Grade 1

2 Intermediate 2-20 3-20Neuroendocrine tumour,

Grade 2

Poorly-

differentiated3 High >20 >20

Neuroendocrine carcinoma,

Grade 3 (small cell)

Neuroendocrine carcinoma,

Grade 3 (large cell)



NON-FUNCTIONING

Non-functioning NETs:

Discovered incidentally during

surgery or on an investigation

being carried out for other

reasons

Do not overproduce hormones

May not cause symptoms


SYMPTOMS

Symptoms:

Pain

Nausea

Change in bowel habits

Lung – chest infections, shortness

of breath, cough, haemoptysis

Overproduction of hormones

(functioning NETs):

Insulinomas – low blood glucose

Glucagonomas – high blood

glucose

VIPomas – diarrhoea

Gastrinomas – ulcers

Image made available under Creative Commons CC0 1.0 Universal Public Domain Dedication.

Some NETs (more commonly NETs of small bowel, large bowel or appendix) may

overproduce serotonin

Serotonin causes a characteristic collection of symptoms called the carcinoid

syndrome


CARCINOID SYNDROME

Investigation Example

Blood tests Routine blood tests -

5-HIAA (serum or urine), chromogranin A, gut hormones, NT proBNP,

neuron-specific enolase

Imaging - Computerised Tomography (CT) scan

- Magnetic Resonance Imaging (MRI)

- Functional imaging - Somatostatin receptor scintigraphy (111-In

pentetreotide [Octreoscan] or Gallium Positron Emission

Tomography (PET) scan)

- Echocardiogram

Biopsy Establish differentiation

Endoscopy Diagnosis, excision

Further tests Bronchoscopy for lung NETs


INVESTIGATIONS

Pancreatic gastrinoma stained for the

somatostatin receptor 2A; the cell membrane

is stained brown (400x magnification)

SOMATOSTATIN RECEPTORS

Somatostatin receptors 2 and 5

(SSTR2 and SSTR5) are expressed in

70-90% of NETs1

Result on somatostatin-receptor

scintigraphy is one factor that predicts

effectiveness of somatostatin

analogue therapy

Outcome according to SSTR

expression not known

1. Papotti M, et al. Expression of somatostatin receptor types 1–5 in 81 cases of gastrointestinal and pancreatic endocrine tumours.

Virchows Arch 2002;440:461–75. Copyright © 2002, Springer-Verlag. With permission of Springer.

68 GALLIUM DOTANOC PET

CT SCAN

Segment 1, 2, 3 and 4 of liver largely

replaced and expanded by tumour

Infiltration of adjacent segments 5 and

8 with multiple smaller discrete tracer

avid lesions in remaining segments

Multiple skeletal lesions

demonstrating intense tracer uptake;

T2 vertebra, right humeral head, left

anterior second rib, sternum, sacrum,

large destructive lesion left scapula

Courtesy of The Christie NHS Foundation Trust

REFERRAL TO SPECIALIST

CENTRE

Because of the rarity of these tumours, not all doctors and local hospitals will have

the full expertise to deal with this type of diagnosis

Referral to a NET centre of excellence may be required

PATIENT

Radiologist

Pathologist

Surgeon

Oncologist

Nurse specialists

Gastroenterologist

Endocrinologist

Co-ordinator

General Practitioner


MULTIDISCIPLINARY MEETING

Depends on:

Primary site of NET

Classification

Size of the tumour and whether it has metastasised

Whether patient has carcinoid syndrome or overproduction of

other hormones

A watch and wait approach may be adopted in selected cases of

incidental NETs


TREATMENT

Management by site:

Gastric

Management depends on type

(whether 1, 2 or 3)

Pancreas

Resection indicated to alleviate

symptoms due to hormone

overproduction, local mass

effect, prevent malignant

transformation or dissemination

Ampulla of Vater

Resection

Small bowel NET

Resection

LOCALISED GASTROINTESTINAL


TREATMENT1

Appendix

<2 cm - simple appendicectomy

(no mesoappendix invasion)

>2 cm or mesoappendiceal

invasion – right hemicolectomy

Rectal NET

<1 cm and T1 – local

endoscopic resection

1-2 cm – controversial –

individualised treatment

required

>2 cm – resection

1. Please refer to European Neuroendocrine Tumour Society (ENETS) guidelines 2016.

Follow-up:

May include:

Biochemical markers (5-HIAA (serum or urine), chromogranin

A, gut hormones, neuron-specific enolase)

Imaging (as appropriate)

Functional imaging (Somatostatin receptor scintigraphy (111-

In pentetreotide [Octreoscan] or Gallium Positron Emission

Tomography (PET) scan) should be performed where

recurrence is suspected

RESECTED GASTROINTESTINAL


FOLLOW-UP1

1. Please refer to ENETS guidelines 2016.

There is no high level evidence to support the role of functional

imaging (somatostatin receptor scintigraphy [111-In pentetreotide

(Octreoscan)] or gallium positron emission tomography [PET] scan)

in response evaluation of patients with advanced gastrointestinal

NETs

ADVANCED GASTROINTESTINAL

NETs: FOLLOW-UP1

1. Please refer to ENETS guidelines 2016.

Treatment goals: (care tailored to suit individual patient)

Remove the tumour by surgery, however, if the tumour has metastasised, this

may not be possible

Alleviate symptoms

Control tumour growth

Maintain patient quality of life


TREATMENT

Courtesy of The Christie NHS Foundation Trust

Hormone Hyper-secretion

Somatostatin analogues

Agents appropriate to specific syndrome

Resectable hepatic metastases Consider surgery

Asymptomatic

Observation alone

Somatostatin analogues at disease

progression or if symptomatic

ADVANCED GASTROINTESTINAL

NETS: INITIAL THERAPY

PROMID1

CLARINET2

SOMATOSTATIN ANALOGUES

1. Rinke A, et al. J Clin Oncol 2009;27:4656–63; 2. Caplin ME, et al. N Engl J Med 2014; 371:224–33.

Log-rank test p < 0.001,

HR = 0.34 (95% CI 0.20-0.59)

RDouble blind

Placebo (n=43)

IM every 28 days

Octreotide LAR (n=42)

30 mg IM every 28 days

Octreotide LAR significantly lengthens

time to tumour progression compared

with placebo in patients with

functionally active and inactive

metastatic midgut NETs

Patients with:

Treatment-naïve

Well differentiated

(95% Ki-67 ≤2%)

Metastatic mid-gut NETs

Primary endpoint:

Time to tumour progression

PROMID:

OCTREOTIDE LAR - PHASE 3

Rinke A, et al., J Clin Oncol. 2009;27:4656-63 Reprinted with permission. © 2009, American Society of Clinical Oncology. All rights reserved.

.

Tumours originated in pancreas,

mid-gut, hindgut or of unknown

origin

96% no tumour progression in 3-6

months before randomisation

84% patients had no previous

treatment

Well differentiated (Ki-67<10%)

Primary endpoint:

Progression-free survival (PFS)

CLARINET:

LANREOTIDE - PHASE 3

Lanreotide is associated with

significantly prolonged PFS among

patients with metastatic

enteropancreatic NETs (Grade 1 or 2)

RDouble blind

Placebo (n=103)

SC every 28 days

Lanreotide (n=101)

120 mg SC every 28 days

From N Engl J Med. 2014, Caplin ME, et al., Lanreotide in Metastatic Enteropancreatic Neuroendocrine Tumors, 371: 224–33. Copyright © 2014,

Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

PFS: According to sub-groups

CLARINET:

LANREOTIDE – PHASE 3

RDouble blind

Placebo (n=103)

SC every 28 days

Lanreotide (n=101)


From N Engl J Med. 2014, Caplin ME, et al. Lanreotide in Metastatic Enteropancreatic Neuroendocrine Tumors, 371:224–33.

Copyright © 2014, Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Median progression-free survival data2

Lanreotide: not reached

Placebo: 12.1 months

(95% CI 9.4-18.3 months)

HR for progressive disease/death 0.58, 95% CI

0.32-1.04

CLARINET1:

LANREOTIDE - PHASE 3 (pNET)

RDouble blind

Placebo (n=49)

SC every 28 days

Lanreotide (n=42)


PFS: According to pNET2 sub-group

Mean age – 64 years both groups

Overall: 37% had hepatic tumour

load >25%, 95% stable disease, 77%

had received no previous treatment,

38% had previous surgery on the

tumour

No new safety concerns

The positive risk-benefit profile for

lanreotide depot in pNETs is

consistent with overall findings in

CLARINET

1. Caplin ME, et al., N Engl J Med. 2014; 371:224-33.

2. Phan AT, et al., J Clin Oncol. 2015; 33 (suppl 3; abstr 233).

Progressive disease

Symptomatic

Somatostatin analogues

Everolimus

Symptomatic from tumour bulkSomatostatin analogues

+/- targeted therapy

Highly symptomatic Chemotherapy1

Hepatic arterial embolisation

Sunitinib

Liver-predominant disease

PANCREATIC NETS:

PROGRESSIVE DISEASE

1. Fine RL, et al., J Clin Oncol . 2014;32 (suppl 3; abstr 179).

Mature median overall survival data2

Everolimus: 44.02 months

(95% CI 35.61-51.75)

Placebo: 37.68 months

(95% CI 29.14-45.77)

HR 0.94, 95% CI 0.73-1.20, P=0.30

Crossover of majority of patients (85%)

may have confounded results.

Everolimus significantly improved PFS as compared to placebo in patients with advanced pNETs

Everolimus: Oral inhibitor of mammalian target of

rapamycin (mTOR)

Patients with:

Advanced, low- or intermediate-grade pNET

40% therapy naïve

Radiologic progression within previous 12 months

Primary endpoint: Progression-free survival

EVEROLIMUS (RADIANT-3)1:

pNET PHASE 3

1. From Yao JC, et al., N Engl J Med. 2011; Everolimus for Advanced Pancreatic Neuroendocrine Tumors; 364:514–23. Copyright © 2011. Massachusetts

Medical Society. Reprinted with permission from Massachusetts Medical Society. 2. Yao JC, et al., ESMO 2014; abstract 11320.

RDouble blind

Placebo (n=203)

Everolimus (n=207)

10 mg/day continuously

OSPFS

2x PFS: 11.4 v 5.5 months

P<0.001

Sunitinib: Multi-targeted tyrosine kinase inhibitor

Patients with:

Well-differentiated advanced pNETs

Majority had received prior systemic therapy

Radiologic progression within previous 12 months

Primary endpoint: Progression-free survival

SUNITINIB: pNET PHASE 3

RDouble blind

Placebo (n=85)

Sunitinib (n=86)

37.5mg/day continuously

Sunitinib improved PFS and OS as compared to placebo in patients with advanced pNETs

From Raymond E, et al., N Engl J Med. 2011; Sunitinib Malate for the Treatment of Pancreatic Neuroendocrine Tumors.

364:501-13. Copyright © 2011. Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Symptomatic from tumour bulkSomatostatin analogues

+/- Chemotherapy

Liver-predominant disease Hepatic arterial embolisation

Refractory to medical therapyPeptide receptor radioligand therapy

(PRRT) – where available

SMALL BOWEL NETS:

PROGRESSIVE DISEASE

Use of targeted radiotherapy using radiolabeled somatostatin analogues, in the

treatment of patients with NETs

Data previously generated in populations of patients with combined pancreatic and

gastrointestinal NETs

In general, objective tumour response rates were up to 30%

Approximately one-third of patients had symptomatic improvement1

PEPTIDE RECEPTOR

RADIONUCLIDE THERAPY: PRRT

1. Kwekkeboom DJ, et al., J Clin Oncol. 2008; 26(13):2124-30.

Evaluate the efficacy and safety of 177Lu-Dotatate plus Octreotide 30 mg compared to

Octreotide LAR 60 mg (off-label use)2 in patients with inoperable, somatostatin receptor positive,

midgut NET, progressive on Octreotide LAR 30 mgAIM

International, multicentre, randomised, comparator-controlled, parallel-groupDESIGN

Treatment and AssessmentsTumour burden assessment (RECIST criteria) every 12 weeks

4 administrations of 7.4 GBq of 177Lu-Dotatate

every 8 weeks + Octreotide 30 mgn = 115

n = 115 Octreotide LAR 60mg every 4 weeks

5 Years

follow up

BASELINE

AND

RANDOMISATION

NETTER-11:

STUDY OBJECTIVES AND DESIGN

1. Strosberg J, et al., ECC Vienna 2015. Abstract 6LBA.

2. FDA and EMA recommendation.

N = 229 (ITT)

Number of events: 90

• 177Lu-Dotatate: 23

• Oct 60 mg LAR: 67

HR [95% CI]

0.209 [0.129 – 0.338]

p < 0.0001

177Lu-Dotatate

Median PFS: Not reached

Octreotide LAR 60 mg

Median PFS: 8.4 months

Significant increase in PFS in patients with advanced midgut NETs

treated with 177Lu-Dotatate

NETTER-1:

PROGRESSION-FREE SURVIVAL

Strosberg J, et al. Presented at the ECC, Vienna, September 2015; abstract 6LBA. Reprinted with permission from Johnathan Strosberg.

Everolimus 10 mg/day

N=205Treated until PD,

intolerable AE, or

consent withdrawal.

Patients with well-differentiated

(G1/G2), advanced, progressive,

nonfunctional NET of lung or GI

origin (N=302).

• Absence of active or any history of

carcinoid syndrome.

• Pathologically-confirmed advanced

disease.

• Radiologic disease progression in ≤ 6

months.

2:1

R

A

N

D

O

M

I

S

E

Placebo

N=97

Endpoints:

• Primary: PFS (central)

• Key Secondary: OS

• Secondary: ORR, DCR, safety, HRQoL (FACT-G), WHO PS, NSE/CgA, PK

Stratified by:

• Prior SSA treatment (yes vs. no)

• Tumour origin (stratum A vs. B)*

• WHO PS (0 vs. 1)

*Based on prognostic level, grouped as: Stratum A (better prognosis) appendix, caecum, jejunum, ileum, duodenum, and NET of unknown

primary. Stratum B (worst prognosis) lung, stomach, rectum, and colon except caecum.

Crossover to open-label everolimus after progression in the placebo arm was not allowed prior to the primary analysis.

RADIANT-4:

STUDY DESIGN

Yao JC, et al., Lancet, 2016; 387:968-77.

52% reduction in the relative risk of progression or death with everolimus vs placebo

HR = 0.48 (95% CI, 0.35-0.67); P < 0.00001

205 168 145 124 101 81 65 52 26 10 3 0 0

97 65 39 30 24 21 17 15 11 6 5 1 0Placebo

Everolimus

No.of patients still at risk

0 2 4 6 8 10 12 15 18 21 24 27 30

Months

0

10

20

30

40

50

60

70

80

90

100

Pro

ba

bilit

y o

f P

rog

res

sio

n-f

ree

Su

rviv

al

(%)

Kaplan–Meier medians

Everolimus: 11.0 months (95% CI, 9.23-13.31)

Placebo: 3.9 months (95% CI, 3.58-7.43)

Censoring Times

Everolimus (n/N = 113/205)

Placebo (n/N = 65/97)

P-value is obtained from the stratified one-sided log-rank test; Hazard ratio is obtained from stratified Cox model.

RADIANT-4:

PROGRESSION-FREE SURVIVAL

Reprinted from Yao JC, et al. Lancet 2016;387:968–77. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or

gastrointestinal tract (RADIANT4): a randomised, placebo controlled, phase 3 study. Copyright 2016, with permission from Elsevier.

Telotristat etiprate is a novel

inhibitor of tryptophan

hydroxylase, the rate-limiting

enzyme in serotonin biosynthesis

TELESTAR1: TELOTRISTAT

ETIPRATE (MECHANISM OF ACTION)

1. Kulke MH, et al., ECC Vienna 2015. Abstract 37LBA.

2. Druce M, et al. Nature Reviews Endocrinology 2009;5:276-283. Reprinted by permission from Macmillan Publishers Ltd:

Nature Reviews Endocrinology Fibrosis and carcinoid syndrome: from causation to future therapy. Copyright 2009.

2

Telotristat etiprate 500 mg TID* (n=45)

Telotristat etiprate 250 mg TID (n=45)

Placebo TID (n=45)

All patients required to be on SSA at enrollment and continue SSA therapy throughout study period

1:1:1

3- to 4-week

run-in (n=135)R

Telotristat

etiprate

500 mg TID

Evaluation of primary endpoint:

Reduction in number of daily BMs from baseline (averaged over 12-

week double-blind treatment phase)

Run in: Evaluation of

bowel movement (BM)

frequency

(well differentiated

metastatic NET with

documented carcinoid

syndrome with ≥4

BMs/day).

TELESTAR:

STUDY DESIGN

Kulke MH, et al., ECC Vienna 2015. Abstract 37LBA.

*Including a blinded titration step of one week of 250 mg TID.

BM; bowel movement, SSA; somatostatin analogue, TID; three times daily.

ClinicalTrials.gov. NCT01677910 TELESTAR. Available at: https://clinicaltrials.gov/ct2/show/NCT01677910. Accessed September 2015.

https://clinicaltrials.gov/ct2/show/NCT01677910

Hodges–Lehmann estimator of treatment differences showed a median reduction versus placebo of

–0.81 BMs daily for telotristat etiprate 250 mg dose (P<0.001)

–0.69 for telotristat etiprate 500 mg dose (P<0.001)

TELESTAR: STUDY DESIGN

Kulke MH, et al., ECC Vienna 2015. Abstract 37LBA. Reprinted with permission from Matthew Kulke.

Systemic chemotherapy with a platinum-based combination regimen, analogous to

that used for small cell lung cancer

Anti-tumoural activity and high tumour response rates (41-67%)1

No established second-line treatment

All studies to date are small retrospective series:

FOLFIRI2 (N=19)

FOLFOX3 (N=21)

Temozolomide-based regimens4 (N=25)

Topotecan5 (N=22)

Taxotere-based chemotherapy6 (N=20)

POORLY-DIFFERENTIATED NE

CARCINOMAS (ADVANCED):

ROLE OF CHEMOTHERAPY

1. Moertel CG, et al., Cancer. 1991;68:227-32; 2. Hentic O, et al., Endocr Relat Cancer. 2012;19:751-7; 3. Hadoux J, et al., ENETS, 2013;

4. Welin S, et al., Cancer. 2011;117:4617-22; 5. Olsen PS, et al., J of Cancer. 2014;5:628-32; 6. Sorbye H, et al., Ann Oncol. 2013;24(1):152-60.

Some ongoing studies1:

Maintenance therapy

Lanreotide as maintenance therapy in patients with non-resectable

duodeno-pancreatic NETs (REMINET – NCT 02288377)

Sequencing of therapy

Everolimus followed by Streptozotocin/5-fluorouracil upon progression or

reverse sequence in pancreatic NET (SEQTOR – NCT 02246127)

Combination therapy with PRRT and chemotherapy

Capecitabine/Temozolomide +/- PRRT in patients with well-differentiated

midgut NETs (NCT 02358356)

THE FUTURE

1. ClinicalTrials.gov

THANK YOU

Optimising Outcomes in Gastrointestinal Neuroendocrine Tumours · of the neuroendocrine system Most...

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